The overall goal of this proposal is to determine whether gender differences contribute to edible plant exosomal non-coding small RNA (nc-sRNA) in the prevention of gut inflammation using the dextran sulfate sodium (DSS) induced colitis mouse models. Our recently published data indicates that exosome-like nanoparticles (ELNs) present in a number of edible plants including grapefruit have anti-inflammatory properties. Mice fed grapefruit ELNs (FELNs) are protected against DSS induced mouse colitis. Up take of FELNs by intestinal macrophages inhibits the release of IL-1? and IL-6 and the induction of HO-1 and IL-10 expression. Our preliminary data further indicate that FELNs carry high levels of specific nc-sRNA that inhibit the induction of proinflammatory cytokines by targeting intestinal macrophages. The nc-sRNA is associated with inactivation of macrophage miR155. A specific FELN nc-sRNA complexed with naringin binds to miR155 and subsequently prevents miR155 binding to 3?UTRs of certain anti-inflammatory genes, thus inhibiting the induction of proinflammatory cytokines. We have also demonstrated that ginger ELN nc-sRNAs promotes the production of IL-10 in lamina propria macrophages under steady-state as well as inflammatory conditions. Therefore, we hypothesize that plant ELNs carrying the nc-sRNA bioactive complex are taken up by intestinal macrophages and subsequently bind to inflammatory microRNAs, resulting in inhibition of induction of chronic inflammation cytokines, thereby preventing chronic intestinal inflammation. Sex is emerging as an important factor in the etiology and expression of many different pathological conditions, and sex-biased disease susceptibility is well demonstrated in different types of illness, in particular inflammation driven immune related diseases. However, whether gender differences contribute to the stability of ELN nc-sRNAs in intestinal macrophages is not known. Our hypothesis will be tested in vitro and in vivo to determine whether sex differences contribute to hormone- depenandet regulation of stability of ELN nc-sRNAs up taken by intestinal macrophages. Demonstration of the hormone-depenandet regulation of ELNs complex targeting to gut inflammatory cells would be a significant step forward in the understanding of how gender differences regulate anti-inflammatory responses through ELNs. The data generated should provide a foundation for selecting specific ELNs from different types of plants for personalized (female versus male) complementary medicine for patients and determine whether oral administration of a customized exosome isolated from different plants will have a synergestic/additive effect on prevention or treatment of disease.